Transcranial Direct Current Stimulation (tDCS) is a non-invasive electrical stimulation technique investigated for a broad range of medical and performance indications. Understanding the cellular mechanisms of tDCS will increase the rigor of ongoing studies and provide a rational basis for dose optimization. Prior mechanistic studies have focused exclusively on direct polarization of neuronal membranes by direct current stimulation (DCS). We propose to test the hypothesis that tDCS directly and transiently modulates blood-brain-barrier (BBB) function, which in turn would modulate neuronal activity. Our approach is to use state-of-the-art animal and tissue models and characterization to determine if a new-class of cellular targets, namely endothelial cells, respond to DCS. These approaches including multi-photon transcranial quantitative imaging of vascular permeability during and after DCS and isolation of molecular and generic responses of endothelial barriers. Because understanding every cellular target of stimulation is required for a comprehensive mechanism, the modulation of BBB by tDCS, in conjunction with direct neuronal effects, is novel and critical to research. This study will be the first to establish the feasibility of direct BBB actions by tDCS as well as quantitatively predict the impact of these changes on neuronal function.